Previous studies on the interactive response system (IRS) have generally adopted the lecture method to facilitate teaching and learning, while few have made efforts to investigate the learning effects of instructional methods and IRS activities on learning and teaching. The purpose of the present study was therefore to explore whether the use of the IRS with two different teaching methods would affect students' learning performance. A quasi-experimental design was employed, with the teacher conducting the course using the learner as leader strategy in the experimental group (E.G.) and the teacher leader strategy in the control group (C.G.). The experiment was conducted over a period of 15 weeks (a semester), and questionnaires were administered at the beginning, in the middle and after the experiment to elicit the learners' views on the IRS application. The results support previous research which found that using the IRS improved learners' engagement and interaction. They also provide further evidence that the use of the IRS with both teaching strategies not only had a short-term learning effect but could also be a tool for sustaining students' learning motivation and self-directed learning for long-term learning purposes. Besides, the use of the learner as leader strategy contributed to enhancing discussion in groups, especially for the leading groups. The use of the IRS with the learner as leader strategy benefited those who acted as leaders in taking the initiative to learn the course content, and also engaged the students who acted as learners in concentrating on the course because it was their classmates who were leading.